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Epidemiology

The incidence of infective endocarditis in the United States increased from 9.3 to 15 per 100,000 from 1998 to 2011. The rapid treatment of group A streptococcal infections in the United States and other developed countries has reduced the case of rheumatic heart disease, a major risk factor for endocarditis. However, in developing countries where resources are limited rheumatic heart disease remains prevalent. One of the leading conditions that predisposes to endocarditis in developed countries is calcific valve disease. This is a disease of the elderly and as life expectancy increases the incidence of calcified heart valves is increasing. The increased use of central intravenous catheters, implantable cardiac devices, and prosthetic cardiac valves as well as the intravenous opioid abuse epidemic also help to explain the rising incidence of endocarditis in developed countries. Males are more likely than females to develop infective endocarditis.

Pathogenesis and Predisposing Risk Factors

Host Factors

Infective endocarditis is usually preceded by the formation of a predisposing cardiac lesion. Preexisting endocardial damage leads to the accumulation of platelets and fibrin, producing nonbacterial thrombotic endocarditis (NBTE). This sterile lesion serves as an ideal site to trap bacteria as they pass through the bloodstream. Cardiac lesions that result in endocardial damage and predispose to the formation of NBTE include rheumatic heart disease, congenital heart disease (bicuspid aortic valve, ventricular septal defect, coarctation of the aorta, and tetralogy of Fallot), mitral valve prolapse, degenerative heart disease (calcific aortic valve disease), and prosthetic valve placement.

Risk factors of endocarditis reflect the pathogenesis of the disease. Patients with congenital heart disease and rheumatic heart disease, those with an audible murmur associated with mitral valve prolapse, and elderly patients with calcific aortic stenosis are all at increased risk. The higher the pressure gradient in aortic stenosis, the greater the risk of developing endocarditis. Intravenous drug abusers are at high risk of developing endocarditis as a consequence of injecting bacterially contaminated solutions intravenously.

Platelets and bacteria tend to accumulate in specific areas of the heart based on the Venturi effect. When a fluid or gas passes at high pressure through a narrow orifice, an area of low pressure is created directly downstream of the orifice. The Venturi effect is most easily appreciated by examining a rapidly flowing, rock-filled river. When the flow of water is confined to a narrower channel by large rocks, the velocity of water flow increases. As a consequence of the Venturi effect, twigs and other debris can be seen to accumulate on the downstream side of the obstructing rocks, in the area of lowest pressure.

Similarly, vegetations form on the downstream or low-pressure side of a valvular lesion. In aortic stenosis, vegetations tend to form in the aortic coronary cusps on the downstream side of the obstructing lesion. In mitral regurgitation, vegetations are most commonly seen in the atrium, the low-pressure side of regurgitant flow. Upon attaching to the endocardium, pathogenic bacteria induce platelet aggregation, and the resulting dense platelet–fibrin complex provides a protective environment. Phagocytes are incapable of entering this site, eliminating an important host defense. Colony counts in vegetations usually reach 109–1011 bacteria per gram of tissue, and these bacteria within vegetations periodically lapse into a metabolically inactive, dormant phase.

The frequency with which the four valves become infected reflects the likelihood of endocardial damage. Shear stress would be expected to be highest in the valves exposed to high pressure, and most cases of bacterial endocarditis involve the valves of the left side of the heart. The mitral and aortic valves are subjected to the highest pressures and are the most commonly infected. Right-sided endocarditis is uncommon (except in the case of intravenous drug abusers), and when right-sided disease does occur, it most commonly involves the tricuspid valve. The closed pulmonic valve is subject to the lowest pressure, and infection of this valve is rare.

Patients with prosthetic valves must be particularly alert to the symptoms and signs of endocarditis, because the artificial material serves as an excellent site for bacterial adherence. Patients who have recovered from an episode of infective endocarditis are at increased risk of developing a second episode.

Bacterial Factors

The organisms responsible for infective endocarditis are sticky. They adhere more readily to inert surfaces and to the endocardium. Streptococci that express dextran on the cell wall surface adhere more tightly to dental enamel and to other inert surfaces. Streptococci that produce higher levels of dextran demonstrate an increased ability to cause dental caries and to cause bacterial endocarditis. Streptococcus viridans, named for their ability to cause green (“alpha”) hemolysis on blood agar plates, often have a high dextran content and are a leading cause of dental caries and bacterial endocarditis. S. mutans and S. sanguis are the species in this group that most commonly cause endocarditis.

One group D streptococcus, S. bovis, produces high levels of dextran and demonstrates an increased propensity to cause endocarditis. This bacterium often enters the bloodstream via the gastrointestinal (GI) tract as a consequence of a colonic carcinoma. S. viridans also express the surface adhesin FimA, and this protein is expressed in strains that cause endocarditis. C. albicans readily adheres to NBTE in vitro and causes endocarditis, particularly in intravenous drug abusers and in patients with prosthetic valves. C. krusei is nonadherent and seldom causes infective endocarditis.

Adherence to specific constituents in the NBTE also may be important virulence characteristics. For example, pathogenic strains of S. sanguis are able to bind to platelet receptors, and endocarditis-causing strains of S. aureus demonstrate increased binding to fibrinogen and fibronectin.

Causes of Bacteremia Leading to Endocarditis

Before bacteria can adhere to NBTE, they must gain entry to the bloodstream. Whenever a mucosal surface heavily colonized with bacterial flora is traumatized, a small number of bacteria enter the bloodstream, where they are quickly cleared by the spleen and liver. As outlined in Table 7-1, there are many causes of transient bacteremia; however, intravascular catheters are the most common cause of bacteremia leading to endocarditis, and 25% of all cases of endocarditis are now hospital acquired. Dental manipulations frequently precipitate transient bacteremia. Patients undergoing dental extraction or periodontal surgery are at particularly high risk, but gum chewing and tooth brushing can also lead to bacteremia. Oral irrigation devices such as the Waterpik should be avoided in patients with known valvular heart disease or prosthetic valves, because these devices precipitate bacteremia more frequently than simple tooth brushing. Other manipulations that can cause significant transient bacteremia include tonsillectomy, urethral dilatation, transurethral prostatic resection, and cystoscopy. Pulmonary and GI procedures cause bacteremia in a low percentage of patients.

Causes of Infective Endocarditis

The organisms most frequently associated with infective endocarditis are able to colonize the mucosa, enter the bloodstream, and adhere to NBTE or native endocardium (see Table 7-2). In native valve endocarditis, in earlier series, Streptococcus species were the most common cause, representing more than half of all cases. S. viridans species were most frequent, followed by S. bovis. However, Staphylococcus species are now the most common cause of native valve endocarditis followed by Streptococcal species. S. aureus predominates, with coagulase-negative staphylococci playing a modest role. Enterococci (S. faecalis and S. faecium) are now classified separately from the streptococci, and in most series, these organisms are the third most common cause of infective endocarditis. Other rarer organisms include gram-negative aerobic bacteria, and the HACEK (Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) group. These slow-growing organisms are found in the mouth and require CO2 for optimal growth. They may not be detected on routine blood cultures that are discarded after 7 days. Anaerobes, Coxiella burnetii (“Q fever endocarditis”), and Chlamydia species are exceedingly rare causes. In about 3–5% of cases, cultures are repeatedly negative.

In intravenous drug abusers, S. aureus and gram-negative organisms predominate as the most common causes (Table 7-2). In certain areas of the country—for example, Detroit, Michigan—methicillin-resistant S. aureus (MRSA) is the predominant pathogen. Pseudomonas aeruginosa, found in tap water, is the most common gram-negative organism. Streptococci also are common, particularly Enterococcus and S. viridans species. Fungi, primarily C. albicans, is another important cause of endocarditis in this population. Polymicrobial disease is also more frequent.

The causes of prosthetic valve endocarditis depend on the timing of the infection (Table 7-2). The development of endocarditis within the first 2 months after surgery (“early prosthetic valve endocarditis”) is primarily caused by nosocomial pathogens. Staphylococcal species (coagulase-positive and negative strains alike), gram-negative aerobic bacilli, and fungi predominate. In disease that develops more than 2 months after surgery (“late prosthetic valve endocarditis”), organisms originating from the mouth and skin flora predominate: S. viridans species, S. aureus, and coagulase-negative staphylococci being most common. Gram-negative aerobic bacilli and fungi are less common, but still important pathogens.

Clinical Manifestations

A 78-year-old retired advertising executive was admitted to the hospital with a chief complaint of increasing shortness of breath and ankle swelling. About 15 weeks before admission, he had some dental work done. About 2 weeks after that work was completed, he began to experience shortness of breath following any physical exertion. He also noted increasing fatigue, night sweats, and intermittent low-grade fever. At that time, a diastolic murmur, II/VI was noted along the left sternal border, maximal at the third intercostal space. He was treated as an outpatient with diuretics for left-sided congestive heart failure (CHF).

The day before admission, he began experiencing increasingly severe shortness of breath. He also began coughing frothy pink phlegm, and he arrived in the emergency room gasping for air.

Physical examination showed a temperature of 39°C, blood pressure of 106/66 mmHg, a pulse of 85 per minute regular, and a respiratory rate of 36 per minute. The patient appeared lethargic and had rapid shallow respirations. His teeth were in good repair. No hemorrhages or exudates were seen in the fundi. With the patients sitting at a 30-degree angle, the jugular veins were distended to the level of his jaw; diffuse wheezes and rales were heard in lower two-thirds of both lung fields. The heart demonstrated a loud S3 gallop, II/VI nearly holosystolic murmur heard loudest in the left third intercostal space radiating to the apex, and a II/VI diastolic murmur heard best along left sternal border. Liver and spleen were not palpable. Pitting edema of the ankles (2+) extending midway up the thighs was noted. Nail beds had no splinter hemorrhages. Pulses were 2+ bilaterally.

Illness script—This 78-year-old man presented with the subacute onset of increasing shortness of breath on exertion accompanied by fever and night sweats. He was noted to have a diastolic heart murmur and was treated with diuretics. Several weeks later he presented with high fever, pulmonary edema on CXR accompanied by an S3 gallop, and both a systolic and diastolic murmur in the aortic area as well as jugular venous distension and pedal edema. He was noted to have modest leukocytosis, normochromic, normocytic anemia, hematuria, an elevated ESR, and a LBBB on EKG. He had undergone a dental procedure 15 weeks before his hospital admission.

History

When the event leading to bacteremia can be identified, the incubation period usually required before symptoms develop is less than 2 weeks. In Case 7-1, the onset of symptoms occurred 15 days after dental work. Because symptoms of endocarditis are usually nonspecific, delays as long as 5 weeks can occur in patients with subacute endocarditis, between the onset of symptoms and diagnosis. In Case 7-1, the delay was 3 months.

As observed in this patient, the most common symptom is a low-grade fever. Body temperature is usually only mildly elevated in the 38°C range. Fever is frequently accompanied by chills and less commonly by night sweats. Fatigue, anorexia, weakness, and malaise are common complaints, and the patient often experiences weight loss. Myalgias and arthralgias are commonly present. Patients with subacute endocarditis are often mistakenly suspected of having a malignancy, connective tissue disease, or other chronic infection such as tuberculosis.

Another prominent complaint in a smaller percentage of patients is low back pain. Debilitating back pain that limits movement can be the presenting complaint, and health care personnel should always consider infective endocarditis as one possible cause of low back pain and fever. Systemic emboli are most common in S. aureus and can result in sudden hemiparesis or sudden limb pain as a consequence of tissue ischemia. In all patients who suffer a sudden cerebrovascular accident consistent with an embolic stoke, infective endocarditis should be excluded.

Acute endocarditis is becoming the most common presentation of endocarditis reflecting the high incidence S. aureus endocarditis. These patients present with a rapid onset (hours to days) of symptoms and signs. In addition to S. aureus, acute endocarditis is associated with enterococci, and occasionally with S. pneumoniae. Fever is often high, 40°C, accompanied by rigors. These patients are usually brought to the emergency room acutely ill. The likelihood of serious cardiac and extravascular complications is higher in these patients, particularly those with acute S. aureus endocarditis. Rapid diagnosis and treatment are mandatory to reduce valvular destruction and embolic complications.

Physical Findings

The classical physical findings of infective endocarditis should be carefully searched for. Fever is the rule and is detected in 96% of patients. A heart murmur is often heard. The absence of an audible murmur should call into question the diagnosis of endocarditis, except in cases of right-sided endocarditis, usually due to IV drug use, or infection of a mural thrombus (rare). Although classically described as a changing murmur, the character of the murmur usually does not change significantly over time unless a valve leaflet is destroyed (occurs most commonly with S. aureus) or a chordae tendineae ruptures. Detection of a new aortic regurgitant murmur is a bad prognostic sign and is commonly associated with the development of congestive heart failure (CHF), as described in Case 7-1. The most common cause of acute aortic regurgitation is infective endocarditis; therefore, if a high-pitched diastolic murmur radiating along the left sternal border is heard, the initial workup should always include blood cultures. In Case 7-1, the diagnosis was delayed because this man’s outpatient physician did not exclude infective endocarditis as the cause of the new diastolic murmur.

Careful attention must be paid to the fundi, skin, nail beds, and peripheral pulses, because manifestations attributable to emboli strongly suggest infective endocarditis. Fundoscopic examination may reveal classic Roth spots, retinal hemorrhages with pale centers, or, more commonly, flame-shaped hemorrhages. One of the most common locations to detect petechial hemorrhages is the conjunctiva (Figure 7-1A). This finding is not specific for endocarditis, being also seen in patients after cardiac surgery and in patients with thrombocytopenia.

Clusters of petechiae can be seen on any part of the body. Other common locations are the buccal mucosa, palate, and extremities. Presence of petechiae alone should be considered a nonspecific finding. The splinter hemorrhages (linear red or brownish streaks) that develop under the nail beds of the hands and feet are caused by emboli lodging in distal capillaries (Figure 7-1B). These lesions can also be caused by trauma to the fingers or toes. Osler nodes are small pea-sized subcutaneous, painful erythematous nodules that arise in the pads of the fingers and toes and in the thenar eminence (Figure 7-1C). They are usually present only for a brief period, disappearing within hours to days. Janeway lesions are most commonly seen in association with S. aureus infection (Figure 7-1D). These hemorrhagic plaques usually develop on the palms and soles. Bacteria can sometimes be visualized on a skin biopsy of the lesion (Figure 7-1D). It must be kept in mind that, as observed in Case 7-1, the majority of patients with infective endocarditis will demonstrate no physical evidence of peripheral emboli. The absence of embolic phenomena therefore does not exclude the diagnosis.

Other findings can include clubbing of the fingers and toes. As a consequence of earlier diagnosis and treatment, this manifestation is less common than in the past, but it may be found in patients with prolonged symptoms. Another commonly reported finding is splenomegaly. Some patients experience left upper quadrant pain and tenderness as a result of splenic infarction caused by septic emboli. Joint effusions are uncommon; however, diffuse arthralgias and joint stiffness are frequently encountered.

Finally, all pulses should be checked periodically. A sudden loss of a peripheral pulse, accompanied by limb pain, warrants immediate arteriography to identify and extract occluding emboli. A thorough neurologic examination must also be performed. Confusion, severe headache, or focal neurologic deficits should be further investigated by computed tomography (CT) or magnetic resonance imaging (MRI) scan with contrast of the head looking for embolic infarction, intracerebral hemorrhage, or brain abscess.

Laboratory Findings

Laboratory abnormalities are nonspecific in nature. Case 7-1 had many of the typical laboratory findings of infective endocarditis. Anemia of chronic disease is noted in 70–90% of subacute cases. A normocytic, normochromic red cell morphology, low serum iron, and low iron binding capacity characterize this form of anemia. Peripheral leukocyte count is usually normal. The finding of an elevated peripheral white blood cell (WBC) count should raise the possibility of a myocardial abscess or another extravascular focus of infection. Leukocytosis is also often found in patients with acute bacterial endocarditis. The erythrocyte sedimentation rate, a measure of chronic inflammation, is almost always elevated. With the exception of patients with hemoglobinopathies that falsely lower the rate of red blood cell sedimentation, the finding of a normal sedimentation rate virtually excludes the diagnosis of infective endocarditis. In nearly all cases, C-reactive protein, another inflammatory marker, is also elevated. A positive rheumatoid factor is detected in half of these patients, and elevated serum globulins are found in 20–30% of cases. Cryoglobulins, depressed complement levels, positive tests for immune complexes, and a false positive serology for syphilis are other nonspecific findings that may accompany infective endocarditis. Urinalysis is frequently abnormal, with proteinuria and hematuria being found in up to 50% of cases. These abnormalities are the consequence of embolic injury or deposition of immune complexes causing glomerulonephritis.

A chest X-ray should be performed in all patients with suspected endocarditis. In patients with right-sided disease, distinct round cannonball-like infiltrates may be detected; these represent pulmonary emboli. In cases of acute mitral regurgitation or decompensated left-sided failure because of aortic regurgitation, diffuse alveolar fluid may be detected, indicating pulmonary edema. Finally, the patient’s electrocardiogram should be closely monitored. The finding of a conduction defect raises concern that infection has spread to the conduction system; in some cases, this spread may progress to complete heart block. In Case 7-1, a left bundle branch block was observed, and this patient subsequently developed complete heart block. Findings consistent with myocardial infarct may be detected when emboli are released from vegetations in the coronary cusps into the coronary arteries.

Diagnosis

Blood Cultures

Blood cultures are the critical test for making a diagnosis of infective endocarditis. As compared with most tissue infections—such as pneumonia and pyelonephritis—that result in the intermittent release of large numbers of bacteria into the blood, infective endocarditis is associated with a constant low-level bacteremia (Figure 7-2). The vegetation is like a time-release capsule, with bacteria being constantly released in small numbers into the bloodstream. It is this constant antigenic stimulus that accounts for the rheumatic complaints and multiple abnormal serum markers associated with infective endocarditis.

To document the presence of a constant bacteremia, blood samples for culture should be drawn at least 15 minutes apart. In patients with suspected subacute infective endocarditis, three blood cultures are recommended over the first 24 hours. In these patients, antibiotics should be withheld until the blood cultures are confirmed to be positive because administration of even a single dose of antibiotics can lower the number of bacteria in the bloodstream to undetectable levels and prevent identification of the pathogen. However, if the patient is acutely ill, 2–3 samples for culture should be drawn over 45 minutes, with empiric therapy begun immediately thereafter.

Because the number of bacteria in the blood is usually low (approximately 100/mL), a minimum of 10 mL of blood should be inoculated into each blood culture flask. Lower volumes reduce the yield and may account for many culture-negative cases. Routinely, blood cultures are held in the microbiology laboratory for 7 days and are discarded if negative. However, if a member of the slow-growing HACEK group is suspected, the laboratory must be alerted to hold the blood cultures for 4 weeks and to subculture the samples on chocolate agar in 5% CO2. If nutritionally deficient streptococci are suspected, specific nutrients need to be added to the blood culture medium.

The sensitivity of blood cultures is excellent, yields being estimated to be 85–95% on the first blood culture and improving to 95–100% with a second blood culture. The third blood culture is drawn primarily to document the constancy of the bacteremia; it does not significantly improve overall sensitivity. The administration of antibiotics within 2 weeks of blood cultures lowers the sensitivity, and patients who have received antibiotics often require multiple blood cultures spaced over days to weeks to identify the cause of the disease.

The Modified Duke Criteria

A definitive diagnosis of infective endocarditis in the absence of valve tissue histopathology or culture is often difficult, and many investigations of this disease have been plagued by differences in the clinical definition of infective endocarditis. Clinical criteria have been established that allow cases to be classified as definite and possible (Table 7-3). Using the modified Duke criteria, a finding of two major criteria, or one major criterion and three minor criteria, or five minor criteria classifies a case as definite infective endocarditis. A finding of one major and one minor criterion, or three minor criteria, classifies a case as possible infective endocarditis.

Complications

In the modern antibiotic era, complications associated with infective endocarditis remain common, with approximately 60% of patients experiencing one complication; 25%, two; and 8%, three or more complications.

Cardiac Complications

Complications involving the heart are most frequent, occurring in one-half of patients. CHF is the most common complication that leads to surgical intervention. Destruction of the valve leaflets results in regurgitation. Less commonly, vegetations become large enough to obstruct the outflow tract and cause stenosis. Perivalvular extension of infection also requires surgical intervention. This complication is more common with aortic valve disease and spread from the aortic valvular ring to the adjacent conduction system can lead to heart block. This complication should be suspected in the infective endocarditis patient with peripheral leukocytosis, persistent fever while on appropriate antibiotics, or an abnormal conduction time or new bundle branch block on electrocardiogram. Transesophageal echo detects most cases, and this test should be performed in all patients with aortic valve endocarditis. Less common complications include pericarditis and myocardial infarction.

Systemic Emboli

Pieces of the vegetation—consisting of a friable collection of platelets, fibrin, and bacteria—frequently break off and become lodged in arteries and arterioles throughout the body. Small emboli are likely released in all cases of endocarditis, but they are symptomatic in only one-sixth to one-third of patients. Patients with large vegetations (exceeding 10 mm) and vegetations on the anterior leaflet of the mitral valve are at higher risk for systemic emboli. Because the right brachiocephalic trunk (innominate artery) is the first vessel to branch from the ascending aortic arch, emboli have a higher likelihood of passing through that vessel and into the right internal carotid artery.

The second branch coming off the aortic arch is the left common carotid artery, and the likelihood of emboli entering this vessel is also higher. These anatomic considerations probably account for the observation that two-thirds of left-sided systemic emboli from the heart lodge in the central nervous system. In addition to sudden neurologic deficits, patients can experience ischemic limbs and splenic and renal infarction.

Mycotic Aneurysms

Infectious emboli can become lodged at arterial bifurcations, where they occlude the vasa vasorum or the entire vessel lumen, damaging the muscular layer of the vessel. The systemic arterial pressure causes ballooning of the weakened vessel wall and formation of an aneurysm. Aneurysms are most commonly encountered in the middle cerebral artery, abdominal aorta, and mesenteric arteries. On occasion, these aneurysms can burst, resulting in intracerebral or intra-abdominal hemorrhage. Because of the increased risk of hemorrhage, anticoagulation should be avoided in patients with infective endocarditis. Mycotic aneurysms are most commonly encountered in S. aureus endocarditis.

Neurologic Complications

Complications arising in the central nervous system are second only to cardiac complications in frequency, being seen in 25–35% of patients. In addition to embolic strokes and intracerebral hemorrhage, patients can develop encephalopathy, meningitis, meningoencephalitis, and brain abscess. In the past, development of a neurologic deficit was considered a contraindication to cardiac surgery. More recent experience indicates that surgery within 1 week of the neurologic event is not accompanied by worsening neurologic deficits.

Renal Complications

Significant renal failure (serum creatinine above 2 mg/dL) can develop in up to one-third of patients, with the likelihood of this complication being higher in elderly patients and in those with thrombocytopenia. Renal dysfunction can be caused by immune complex glomerulonephritis, renal emboli, and drug-induced interstitial nephritis. Glomerulonephritis results from deposition of immune complex in the basement membranes of the glomeruli, resulting in the microscopic changes of membranoproliferative disease. Urinalysis reveals hematuria and mild proteinuria. Red cell casts are observed in glomerulonephritis, but not in interstitial nephritis. Glomerulonephritis usually improves rapidly with antibiotic therapy.

Treatment

Antibiotics

Whenever possible, the antibiotic therapy of subacute infective endocarditis should be based on the antibiotic sensitivities of the offending organism or organisms (Table 7-4 lists doses). Because bacteria are protected from neutrophil ingestion by the dense coating of fibrin found in the vegetation, bactericidal antibiotics are required to cure this infection. To design the most effective regimen, minimal inhibitory concentration levels should be determined for multiple antibiotics, and combinations of these antibiotics tested for synergy (see Chapter 1). The goal is to achieve the highest possible concentrations of cidal antibiotic activity in the blood stream; therefore, maximum doses of antibiotics should be used whenever possible taking into account potential toxicities.

Table 7-4Modified Duke Criteria for the Diagnosis of Infective Endocarditis

Major Criteria

Minor Criteria

Definite Infective Endocarditis

Possible Infective Endocarditis

1. Two separate blood cultures, both positive for typical endocarditis-associated organisms, including Staphylococcus aureus OR Persistent positive blood cultures—two more than 12 hours apart, or three, or a majority from among more than four, during 1 hour

A second important principle of antibiotic therapy is the requirement of prolonged treatment. The concentrations of bacteria in the vegetation are high, and a significant percentage of the bacteria slow their metabolism and stop actively dividing for significant periods. These conditions prevent immediate sterilization by antibiotics that require active bacterial growth for their action (penicillins, cephalosporins, and glycopeptide antibiotics). To prevent relapse, most curative regimens are continued for 4–6 weeks. One exception is uncomplicated subacute bacterial endocarditis caused by S. viridans species. The combination of penicillin G and gentamicin is synergistic and is associated with more rapid killing of bacteria in vegetations. Combination therapy for 2 weeks results in cure rates similar to those with penicillin alone for 4 weeks. A 2-week course of ceftriaxone and gentamicin achieves comparable results. The gentamicin dose should be adjusted to maintain peak serum levels of 3 μg/mL, the concentration required to achieve synergy.

In acute bacterial endocarditis, intravenous empiric antibiotic therapy should be initiated immediately after two to three blood samples for culture have been drawn. The combination of vancomycin, ampicillin, and gentamicin is recommended to cover the most likely pathogens (S. aureus, including MRSA; S. pneumoniae; and enterococci), pending culture results. Empiric therapy for culture-negative subacute bacterial endocarditis should include ampicillin and gentamicin to cover for enterococci, the HACEK group, and nutritionally deficient streptococci.

Table 7-5 outlines the regimens for each specific bacterial cause of endocarditis. Whenever possible, a synergistic regimen consisting of a β-lactam antibiotic and an aminoglycoside is preferred. One exception to this rule is native valve endocarditis caused by S. aureus. Combination therapy with nafcillin or oxacillin and gentamicin has not been shown to improve mortality or overall cure rates, and therefore dual antibiotic therapy is not recommended. With the exception of ceftazidime, minimum inhibitory concentrations (MICs) for cephalosporins correlate well with therapeutic response, and these agents are often therapeutically equivalent to the semisynthetic penicillins. The β-lactam antibiotics are preferred over vancomycin because vancomycin is less rapidly cidal, and failure rates of up to 40% have been reported when S. aureus endocarditis is treated with vancomycin. Daptomycin has been shown to be noninferior to vancomycin in MRSA bacteremia and right-sided endocarditis. In the penicillin-allergic patient with methicillin-sensitive S. aureus endocarditis, β-lactam desensitization should be strongly considered. In patients with enterococcal endocarditis maximal doses of intravenous penicillin or ampicillin combined with gentamicin are preferred, and this combination is recommended for the full course of therapy. However, one series noted comparable cure rates when gentamicin was administered for the first 2 weeks of therapy. In patients with creatinine clearances of <50 mL/min, the combination of ampicillin and ceftriaxone is preferred over ampicillin and gentamicin. This combination of two β-lactam antibiotics achieved similar cure rates in two limited clinical trials. Vancomycin combined with gentamicin is a suitable alternative in the penicillin-allergic patient. With the exception of uncomplicated infection with S. viridans species, antibiotic treatment should be continued for 4–6 weeks.

Antibiotic therapy for prosthetic valve endocarditis presents a particularly difficult challenge. The deposition of biofilm on the prosthetic material makes cure with antibiotics alone difficult, and the valve often has to be replaced. Some patients with late-onset prosthetic valve endocarditis caused by very antibiotic-sensitive organisms can be cured by antibiotic treatment alone. In patients with coagulase-negative staphylococci, a combination of intravenous vancomycin (1 g twice daily) and rifampin (300 mg three times daily) for more than 6 weeks, plus gentamicin (1 mg/kg three times daily) for 2 weeks, is the preferred treatment of methicillin-resistant strains. For methicillin-sensitive strains, nafcillin or oxacillin (2 g every four hours) should be substituted for vancomycin.

Surgery

Medical therapy alone is often not curative, particularly in prosthetic valve endocarditis. In a significant percentage of patients, surgical removal of the infected valve or debridement of vegetations greatly increases the likelihood of survival. As a consequence, in recent years, the threshold for surgery has been lowered. Because of problem of recidivism, surgery should be avoided whenever possible in patients using intravenous drugs.

In almost all cases of infective endocarditis, the cardiologist and cardiac surgeon should be consulted early in the course of the illness. The decision to operate is often complex, and appropriate timing of surgery must balance the risk of progressive complications with the risk of intraoperative and postoperative morbidity and mortality. Indications for surgery include the following:

Moderate-to-severe CHF. CHF is the most frequent indication for surgery. A delay in surgery often results in a fatal outcome because of irreversible left ventricular dysfunction. In patients with CHF death can be very sudden.

More than one systemic embolus. The ability to predict the likelihood of recurrent emboli by echocardiography is questionable. In some studies, large vegetations (exceeding 10 mm in diameter) and vegetations on the anterior leaflet of the mitral valve were found to have a higher probability of embolizing.

Uncontrolled infection.S. aureus is one of the most common pathogens to cause persistently positive blood cultures. Extravascular foci of infection should always be excluded before surgical intervention is considered.

Resistant organisms or fungal infection. The mortality in fungal endocarditis approaches 90%, and with the exception of a rare case of C. albicans, cures have not been achieved by medical therapy alone.

Perivalvular/myocardial abscess. With the exception of very small abscesses, these lesions usually enlarge on medical therapy and require surgical debridement and repair. Heart block is a caused by the extension of infection beyond the endocardium into the electrical conduction system and is an indication for early surgery.

Severe valve regurgitation and mobile vegetation >10 mm has recently been added as an indication for early surgery.

Mobile vegetations >10 mm. Early surgery may be considered in these patients particularly when the vegetation is located on the anterior leaflet of the mitral valve.

As discussed earlier in “Neurologic complications” section, a focal neurologic deficit is not an absolute contraindication to surgery. Whenever possible, surgery should be delayed until blood cultures are negative to reduce the risk of septic intraoperative complications. However, even in the setting of ongoing positive blood cultures, infection of the new valve is uncommon, particularly if the surgeon thoroughly debrides the infected site. Relapse following surgery is rare (0.8%) and has not been shown to be related to positive blood cultures at the time of surgery or to positive valve cultures. Identification by PCR of the bacterial cause of valve tissue infection is a promising experimental method that should make diagnosis and treatment of culture-negative bacterial endocarditis more accurate.

Prognosis

The overall 6-month mortality associated with native and prosthetic endocarditis is 22–27%. Cure rates depend on the organism involved and the valve infected. S. aureus remains a particularly virulent pathogen and continues to be associated with a 50% mortality in patients over the age of 50 years. Patients with an infected aortic valve accompanied by regurgitation also have a 50% mortality. Fungal infections and infections with gram-negative aerobic bacilli are associated with poor outcomes. Development of CHF or onset of neurologic deficits is associated with a worse prognosis. Patients with early prosthetic valve endocarditis often do poorly despite valve replacement, with cure rates ranging from 30% to 50%. Late prosthetic valve endocarditis has a better outcome. In patients with late prosthetic valve infection with S. viridans species, cure rates of 90% have been achieved when antibiotic therapy is accompanied by surgery and 80% with antibiotic treatment alone. Patients with S. epidermidis late prosthetic valve endocarditis have been cured 60% of the time medically, and they have a 70% cure rate when medical treatment is combined with valve replacement.

Prevention

The efficacy of prophylaxis for native valve endocarditis has never been proven. As documented in Table 7-1, individuals probably experience multiple episodes of transient bacteremia each day, and this cumulative exposure is hundreds of times greater than a single procedure. As a consequence of these concerns, the American Heart Association now recommends antibiotic prophylaxis only for high-risk patients. High-risk patients are defined as patients with prosthetic valves (including bioprosthetic and homograft valves), a history of endocarditis, complex cyanotic congenital heart disease, or surgically constructed systemic pulmonary shunts.

The timing of antibiotic prophylaxis is important. The antibiotic should be administered before the procedure and timed so that peak serum levels are achieved at the time of the procedure. Table 7-6 outlines the suggested agents and schedules.

CENTRAL VENOUS CATHETER INFECTIONS

Epidemiology and Pathogenesis

Annually, over 250,000 catheter-related bloodstream infections are reported in the United States. These infections cost an average of $35,000 per episode and can be associated with mortality rates as high as 35%. Bacteria most commonly infect catheters by tracking subcutaneously along outside of the catheter into the fibrin sheath that surrounds the intravascular segment of the catheter. Bacteria can also be inadvertently introduced into the hub and lumen of the catheter from the skin by a caregiver or as a consequence of a contaminated infusate. Less commonly, catheters can be infected by hematogenous spread caused by a primary infection at another site.

Once bacteria invade the fibrin sheath surrounding the catheter, they generate a biofilm that protects them from attack by neutrophils. This condition makes sterilization by antibiotics alone difficult. The risk of infection is greater for some devices than others:

The organisms most commonly associated with intravascular device infection are skin flora. Gram-positive cocci predominate, with coagulase-negative staphylococci being most common, followed by S. aureus. Coagulase-negative staphylococci produce a glycocalyx that enhances its adherence to synthetic materials such as catheter tips. Enterococci is third most common gram-positive pathogen, less frequently corynebacteria, and bacillus may be cultured. Gram-negative bacilli account for up to one-third of infections, with Klebsiella pneumoniae, Enterobacter species, E. coli, Pseudomonas species, Acinetobacter species, and Serratia species being most common. Positive blood cultures for Klebsiella, Citrobacter, and non-aeruginosa strains of Pseudomonas suggest a contaminated infusate.

Fungi now account for 20% of central venous catheter infections, C. albicans predominating. Like coagulase-negative staphylococci, C. albicans is able to form a glycocalyx that enhances adherence to catheters. Patients receiving high glucose solutions for hyperalimentation are at particularly high risk for this infection.

Clinical Manifestations and Diagnosis

A 53-year-old white woman was admitted to the hospital with complaints of severe shaking during infusion of her hyperalimentation solution. She had been receiving intravenous hyperalimentation for 16 years for a severe dumping syndrome that prevented eating by mouth. She had multiple complications from her intravenous lines, including venous occlusions and line-associated bacteremia, requiring 24 line replacements. She had last been admitted 6 months earlier with Enterobacter cloacae infection of her central venous line requiring line removal and intravenous cefepime. At that time, a tunneled catheter had been placed in her left subclavian vein, and she had been doing well until the evening before admission. As she was infusing her solution, she developed rigors, and her temperature rose to 39.2°C. She continued to experience chills and developed a headache.

On physical examination, her temperature was found to be 38°C and her blood pressure 136/50 mmHg. She was nontoxic appearing. A II/VI systolic ejection murmur was noted along the left sternal border (present for years). The site of the catheter was not erythematous or tender. Two blood cultures were positive for Escherichia coli. The sample from the catheter became culture-positive 6 hours after being drawn, and a simultaneous peripheral blood sample became culture-positive 5 hours later (11 hours after being drawn).

Illness script—This 53-year-old female with a history of recurrent central line infections presented with the acute onset of fever and rigors during infusion of her hyperalimentation solution. On exam she had a temperature of 38°C and she was normotensive and nontoxic and had a systolic ejection murmur.

The clinical presentation of central venous line (CVL) infection is nonspecific, generally involving fever, chills, and malaise. The finding of purulence around the intravascular device is helpful, but this sign is not always present. The absence of an alternative source for bacteremia should always raise the possibility of a CVL infection. As observed in Case 7-2, the abrupt onset of chills or hypotension during infusion of a solution through the CVL strongly suggests catheter-associated infection or contamination of the infusate. The rapid resolution of symptoms following removal of the device, plus positive blood cultures for coagulase-negative staphylococci, Staphylococcal aureus, a gram-negative bacillus or a fungus are other findings that suggest an infected CVL.

Purulence around the catheter site provides strong evidence, but this sign is absent in many cases.

Blood samples for culture should be drawn simultaneously from the catheter and the peripheral veins.

Positive bacterial growth from a catheter >2 hours before positive growth in a peripheral sample indicates catheter infection. This test has high specificity (100%), but low sensitivity (42%); therefore, a negative test does not exclude catheter infection.

Roll and sonication methods can be used for quantitating bacteria on the catheter tip. Surveillance cultures are not recommended.

When a CVL infection is suspected, at least two and preferably three blood samples for culture should be drawn: one set from the intravenous catheter and one to two sets from the peripheral veins. A negative blood culture from a sample drawn from the intravenous line is very helpful in excluding the diagnosis of catheter-related bloodstream infection. A positive culture requires clinical interpretation.

One approach for differentiating central line infection from a peripheral source of bacteremia (used in Case 7-2) takes advantage of the automated colorimetric continuous monitoring of blood cultures now available in most clinical microbiology laboratories. The time required to detect bacteria in the catheter sample is compared with the time required in the peripheral sample. Detection of bacteria in the catheter sample >2 hours before the peripheral sample suggests a catheter-associated infection. The cut-off of 120 minutes is highly specific for a central line infection (100% specificity); however, this cut-off time is associated with high number of false-negative interpretations (sensitivity only 42%). Therefore, a positive result is helpful, but a negative result does not exclude CVL infection. In Case 7-2, the history of rigors during intravenous infusion combined with the earlier detection of bacteria in the catheter culture than in the peripheral culture provided strong evidence that the infection originated in the CVL.

If the catheter is removed the tip should be cultured, and two methods for testing the catheter are recommended. The roll method (catheter is rolled across the culture plate) is semiquantitative (positive with 15 cfu or more); the vortex or sonication method (releases bacteria into liquid media) is quantitative (positive with 100 cfu or more). The roll method detects bacteria on the outer surface of the catheter; the vortex or sonication method also detects bacteria from the lumen. The sonication method is more sensitive, but more difficult to perform than the roll method. The use of antibiotic- and silver-impregnated catheters may lead to false-negative results with these methods. Cultures of removed catheter tips should be performed only when a catheter-related bloodstream infection is suspected. Routine surveillance culturing of removed catheter tips is not recommended.

Treatment

Empiric antibiotic therapy should be initiated after appropriate cultures have been obtained. Vancomycin is usually recommended to cover for MRSA and for methicillin-resistant coagulase-negative staphylococci. In the severely ill or immunocompromised patient, additional coverage for gram-negative bacilli is recommended: a fourth-generation (cefepime) cephalosporin or a semisynthetic broad-spectrum penicillin with a β-lactamase inhibitor (piperacillin–tazobactam) should be prescribed. In the severely ill patient, the catheter should be removed immediately. The catheter should also be removed if fever persists and blood cultures continue to be positive beyond 48 hours, and if the patient is infected with virulent, and/or difficult-to-treat pathogens (S. aureus; bacillus, micrococcus species, P. aeruginosa multi-resistant gram-negative bacilli, and fungi). Polymicrobial bacteremia suggests heavy contamination of the line and usually warrants catheter removal. Other indications for removal include neutropenia, tunnel or pocket infection, valvular heart disease or endocarditis, septic thrombophlebitis, or the presence of metastatic abscesses.

The duration of therapy has not been examined in carefully controlled trials. Therapy is usually continued for 10–14 weeks in uncomplicated infection. For patients with coagulase-negative staphylococci, treatment for 5–7 days is sufficient if the catheter is removed, but treatment should be continued for a minimum of 2 weeks if the catheter is left in place. In complicated infections in which bacteremia continues despite removal of the catheter, treatment must be continued for 4–6 weeks. Because of the high incidence of relapse, follow-up blood cultures are important if the infected line was kept in place.

The salvage rate for tunnel catheters can be improved by filling the catheter lumen with pharmacologic concentrations of antibiotic—termed “antibiotic lock therapy.” For coagulase-negative staphylococcus, vancomycin (25 mg in 5 mL of solution) is usually recommended, and for gram-negative bacilli, gentamicin (5 mg in 5 mL) is the agent of choice. This treatment exposes the bacteria to very high concentrations of antibiotic that are more likely to penetrate the biofilm. Antibiotic lock therapy is particularly helpful in tunnel catheters, because the associated infections usually develop within the catheter lumen. Cure rates from 60% to 80% have been achieved in patients with coagulase-negative staphylococcus and antibiotic-sensitive gram-negative bacilli. Antibiotic lock therapy is not helpful for extraluminal infections or for the treatment of S. aureus, P. aeruginosa, drug-resistant gram-negative bacilli, or Candida.

Because of the ability of S. aureus to attach to and destroy normal heart valves (70% of S. aureus endocarditis cases occur on previously normal heart valves), infection with this pathogen poses a unique challenge. The duration of therapy after prompt catheter removal is best guided by TEE. The presence of valvular vegetations on TEE warrants 4 weeks of therapy; the absence of vegetations by this test allows treatment to end after 2 weeks without significant risk of relapse. Short-course therapy should be considered only in patients who promptly defervesce on antibiotic therapy and who do not have valvular heart disease or an extravascular focus of infection.

In patients infected with Candida species, the intravenous catheter must be removed. Because of the high risk of Candida endophthalmitis (10–15%), catheter removal must be accompanied by antifungal therapy. In uncomplicated C. albicans infection, an echinocandin is recommended (anidulafungin, caspofungin, or micafungin). Therapy with systemic liposomal amphotericin B may be warranted in patients with persistent fungemia and severe systemic complaints, or neutropenia.

Prevention

A specialized team dedicated to placing CVLs has been shown to reduce the incidence of CVL infection. Use of a checklist to assure that five specific conditions are fulfilled has proved effective in reducing CVL infection throughout the state of Michigan from 7.7 to 1.4 infections per 1000 days.

Regular exchange of central venous catheters over guide wires does not reduce the incidence of infection. In fact, reinsertion of a catheter through an infected soft-tissue site can precipitate bacteremia. Antibiotic impregnation of central line catheters is another approach to reducing CVL infections and has been associated with a reduction in incidence of infection and colonization, but has not been accompanied by a decrease in mortality as compared to non-impregnated catheters.

Pathogenesis

Inflammation of the pericardium has multiple infectious and noninfectious causes. Of cases in which a cause can be determined, a virus is most common. The same viruses that invade the myocardium also attack the pericardium. Bacteria can also cause pericarditis, resulting in purulent disease. In the antibiotic era, pericarditis has become rare. S. aureus, S. pneumoniae, and other streptococci are the leading causative organisms, although virtually any bacterium can cause purulent pericarditis. The pericardium can become infected as a result of hematogenous spread (the most common route today) or by spread from a pulmonary, myocardial, or subdiaphragmatic focus. Purulent pericarditis can also be a delayed complication of a penetrating injury or cardiac surgery. Postoperative infections are most commonly caused by S. aureus, gram-negative aerobic rods, and Candida species.

Tuberculous pericarditis results from hematogenous spread during primary disease, from lymphatics draining the respiratory tract, or from direct spread originating in the lung or pleura. Initially, infection causes fibrin deposition and development of granulomas containing viable mycobacteria; gradual accumulation of pericardial fluid—initially containing polymorphonuclear leukocytes, and then eventually lymphocytes, monocytes, and plasma cells—follows. Finally, the effusion is absorbed, and the pericardium thickens, becomes fibrotic, and calcifies. Over time, the pericardial space shrinks, causing constrictive pericarditis.

Clinical Manifestations

Clinical manifestations of pericarditis vary depending on the cause. Viral and idiopathic pericarditis usually present with substernal chest pain, which is usually sharp and made worse by inspiration. Pain is also worsened by lying supine, the patient preferring to sit up and lean forward. In acute bacterial pericarditis, the patient suddenly develops fever and dyspnea, and only one-third of patients complain of chest pain. Because of the lack of specific symptoms, a diagnosis of purulent pericarditis is often not considered, and the diagnosis is made only at autopsy. Tuberculous pericarditis is more insidious in clinical onset. Vague, dull chest pain, weight loss, night sweats, cough, and dyspnea are most commonly reported.

The classic physical findings of pericarditis include a scratchy three-component friction rub (as a result of the moving heart rubbing against the abnormal pericardium during atrial systole), early ventricular filling, and ventricular systole. When the pericardial effusion increases in volume, the friction rub usually disappears. The hemodynamic consequences of the pericardial effusion can be assessed by checking for pulsus paradoxus; a value exceeding 10 mmHg indicates significant tamponade. A second hemodynamic consequence of pericardial tamponade is a rise in right ventricular filling pressure. High right-sided pressure causes an increase in jugular venous distension. The patient often has a rapid respiratory rate and complains of dyspnea. However, because of the equalization of right- and left-sided cardiac pressures, pulmonary edema does not develop, and the lung fields are clear on auscultation.

Diagnosis and Treatment

Electrocardiogram is abnormal in 90% of patients and may show diffuse ST segment elevation, depression of the PR segment, and (when the effusion is large) decreased QRS voltage and electrical alternans. The electrocardiography findings are usually not specific, and when pericarditis is being considered, echocardiography is the critical test that needs to be ordered. The echocardiogram readily detects pericardial thickening and pericardial fluid accumulation. In life-threatening tamponade, echocardiography can be used to guide pericardiocentesis. In the absence of hemodynamic compromise, pericardiocentesis is not recommended because of the low diagnostic yield and moderate risk of the procedure. However, in patients with significant pericardial tamponade, pericardial fluid yields a diagnosis in one-quarter of cases, and pericardial biopsy in half of patients. Pericardial fluid and tissue biopsy can be performed surgically. In an emergency, echocardiography-guided catheter pericardiocentesis can be performed. In patients with a thickened pericardium, a percutaneous pericardial biopsy can safely be performed.

Viral and idiopathic pericarditis are usually benign self-limiting disorders that can be treated with bed rest. Nonsteroidal anti-inflammatory agents are helpful for reducing chest pain, but they should probably be avoided in patients with accompanying myocarditis. Colchicine (1 mg daily) may also be helpful for reducing symptoms in cases of idiopathic disease.

In patients with purulent pericarditis, surgical drainage of the pericardium should be performed emergently, accompanied by systemic antibiotic therapy. This disease continues to be accompanied by a 30% mortality.

Tuberculous pericarditis should receive four-drug antituberculous therapy. However, during treatment, 20–50% of patients progress to constrictive pericarditis. This complication can be prevented by simultaneous administration of oral prednisone (60 mg for 4 weeks, 30 mg for 4 weeks, 15 mg for 2 weeks, and 5 mg for 1 week). Patients who have developed calcific tuberculous pericarditis at the time of diagnosis require pericardiectomy for relief of symptoms.